Abstract Strokes account for one out of every 19 deaths in the United States and the cost for cardiovascular disease and strokes in 2009 was $312 billion dollars (compared to $228 billion for all cancers). Cerebral small vessel diseases (SVD) account for up to 30% of strokes and are a leading cause of age-related cognitive decline and disability. Rare mutations in the genes encoding collagen type IV alpha 1 (COL4A1) cause inherited SVD including leukoaraiosis, subcortical microbleeds, porencephaly, intracranial aneurysms, enlarged perivascular spaces, lacunar infarctions and hemorrhagic strokes. Common COL4A1 variants have been associated intracranial aneurysms, arterial calcification, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and leukoencephalopathy. How COL4A1 mutations cause SVD is unknown and represents a significant gap in our current knowledge. This proposal represents an integrated and holistic approach to understand SVD pathogenesis. The goal of our diverse team is to identify novel SVD etiologies and pathogenic mechanisms that can be targeted to prevent, delay or reduce damage from SVD. Our specific focus is on the intracellular and extracellular consequences of COL4A1 mutations, yet, we also have the potential to identity novel SVD subclasses and break open unrelated areas of research.